tbuckley/cabot-search huggingface dataset:
P11.13.A FREQUENCY AND SURVIVAL OUTCOMES OF MOLECULAR GLIOBLASTOMA IN IDH-WILD HISTOLOGICALLY LOWER-GRADE GLIOMAS: A SYSTEMATIC REVIEW AND META-ANALYSIS
Authors: S Nakasu, S Deguchi, Y Nakasu
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND The WHO 2021 classification defines IDH wild-type (IDHw) histologically lower-grade glioma (hLGG) as molecular glioblastoma (mGBM) if TERT promotor mutation (pTERTm), EGFR amplification or chromosome 7 gain and 10 loss aberrations are indicated. However, majority of studies reported that patients with mGBM were likely to undergo biopsy rather than resection and less likely to receive adjuvant radiochemotherapy. Thus, while most studies have suggested the prognostic correspondence between hGBM and mGBM, the equivalence has not been sufficiently demonstrated. Furthermore, molecular marker frequency in IDHw hLGGs differ extensively between studies (pTERTm rates = 15% to &amp;gt;70%). It is unclear if such differences are caused by methodological or other factors, however, differences may affect tumor classification and prognostication. MATERIAL AND METHODS We systematically reviewed articles of IDHw hLGGs studies in PubMed, Ovid MEDLINE, Cochrane library and Scopus, andmeta-analyzed mGBM prevalence and overall survival (OS) according to the PRISMA statement. RESULTS We selected 49 studies (N = 3748) for the analyses. mGBM rates in IDHw hLGG were significantly lower in Asian regions (43.7%, 95% confidence interval [CI: 35.8-52.0]) when compared with non-Asian regions (65.0%, [CI: 52.9-75.4]) (P = 0.005). IDHw hLGGs without pTERTm rarely expressed other molecular markers in Asian studies when compared with non-Asian studies. We compared OS rates of IDHw hLGG tumors between Asian and non-Asian studies using individual patients’ data. The median OS rate in Asian mGBM tumors (21.1 months [CI: 16.1-24.7]) was similar to in non-Asian tumors (20.8 months [CI: 17.9-22.7]) (P = 0.45). Patients with mGBM had significantly longer OS times when compared with histological GBM (hGBM) (pooled hazard ratio (pHR) in univariate analyses 0.824, [CI: 0.694-0.98], P = 0.028, I2 = 46%)). Moderate heterogeneity improved in the pooled HR in multivariate analyses, which showed a significantly better OS in mGBM (HR 0.61 [CI: 0.50-0.74], I2 = 0%) (P &amp;lt; 0.0001). In patients with mGBM, histological grade was a significant prognostic factor (P = 0.018), as was age (P = 0.001) and surgical extent (P = 0.018). CONCLUSION Patients with mGBM have better OS when compared with patients with hGBM, especially when grade II histology is indicated. We identified differences between Asian and non-Asian regions in terms of molecular marker frequency pattern for mGBM in IDHw hLGG. However, OS rates in patients with mGBM were concordant between Asian and non-Asian cohorts.
P11.04.B ASSESSMENT OF TUMOR ELOQUENCE IN GLIOMA RESECTIONS: A SYSTEMATIC REVIEW
Authors: E Rammeloo, J W Schouten, K Krikour, E M Bos, M S Berger, J K W Gerritsen, A J P E Vincent
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Tumor location and eloquence are two crucial factors when deciding on the optimal surgical strategy in glioma management. Consensus is currently lacking on the assessment and definition of eloquent areas. This systematic review aims to evaluate the existing definitions and assessment methods of eloquent areas used in current clinical practice. MATERIAL AND METHODS A computer-aided search of Embase, Medline (OvidSP), and Google Scholar was performed to identify relevant studies. This review includes articles describing preoperative definitions of eloquence in the study’s Methods section. These definitions were compared and categorized by anatomical structure. Additionally, various techniques to preoperatively assess tumor eloquence were extracted, along with their benefits, drawbacks and ease of use. RESULTS This review covers 98 articles including 12,714 participants. Evaluation of these studies indicated considerable variability in defining eloquence. Categorization of these definitions yielded a list of 32 brain regions that were considered eloquent. The most commonly used methods to preoperatively determine tumor eloquence were anatomical classification systems and structural MRI, followed by DTI-FT, functional MRI and nTMS. CONCLUSION None of the definitions or techniques to define eloquence described in the articles are entirely satisfactory as an objective, quantifiable, preoperative factor in glioma treatment and surgical decision-making. Therefore, we propose the development of a new, easily applicable and interpretable anatomical preoperative grading system to assess tumor eloquence. This may aid neurosurgeons in their perioperative decision-making to improve surgical outcomes on an individual patient level and to facilitate the execution and interpretation of multicenter studies.
P14.07.B CELL-FREE DNA IN LONGITUDINALLY-ACQUIRED CEREBROSPINAL FLUID FOR DISEASE MONITORING
Authors: C Riviere-Cazaux, W Mo, X Dong, S Luo, A Wang, P Du, K Ghadimi, A Warrington, T Burns
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Few methods exist via which to assess treatment response with high fidelity in gliomas. Cell-free DNA (cfDNA) is of growing interest as a liquid biomarker in plasma and CSF and has been used in other cancer types to optimize therapeutic regimens for individual patients. While CSF has previously been used as a source of cfDNA for gliomas, it remains unknown how cfDNA abundance and sequencing change throughout treatment and inevitable recurrence. To that end, we leveraged our growing biobank of longitudinal CSF specimens, acquired via CSF access devices, to determine the potential utility of CSF cfDNA as a monitoring tool for treatment response in patients with gliomas. MATERIAL AND METHODS Longitudinal CSF specimens were acquired via Ommaya reservoirs (NCT04692337) or ventriculoperitoneal shunts (NCT04692324) in patients with brain tumors, including gliomas. cfDNA was extracted from 1-5 mL of CSF based on available sample volumes and quantified via Qubit. Next-Generation sequencing (PredicineCARE) or low-pass whole genome sequencing (LPWGS) was performed by Predicine, Inc based on the amount of cfDNA available. RESULTS CSF acquired prior to versus after resection demonstrated an increase in quantified cfDNA (2.97x, range: 1.58-5.26x), consistent with the impact of increased parenchymal disruption and closer contact with CSF. Thereafter, CSF cfDNA continued to decrease throughout chemoradiation and adjuvant treatment and increased at recurrence, including in patients co-enrolled in immunotherapy trials for IL-7 agonists and pembrolizumab. Interestingly, copy number burden (CNB) increased by the time of recurrence in three patients with known disease progression, and continued to decrease throughout immunotherapy treatment in one patient despite concerns of pseudoprogression. In one patient with a hypermutated glioblastoma, CSF cfDNA revealed over 59 genomic alterations, including MAP2K1, KIT, and PDGFRA, and over 100 more variants of unknown significance, each of which had been detected in sequencing of the tissue acquired at resection and subsequently decreased with chemoradiation. In another patient with a known progressing EGFR-amplified GBM, over 200 new variants were identified by the patient’s final sample and EGFR copy number increased from 2 to over 30. CONCLUSION Analysis of cfDNA over a patient’s disease course, including resection and treatment with standard-of-care and experimental therapies, may be of use for disease monitoring and treatment response. Further work is needed to evaluate these findings in a larger cohort of patients and to determine the sensitivity of changes in mutations, CNB, and cfDNA quantity for glioma disease burden.
JS01.3.A EPIGENETICALLY DEFINED ANGIOCENTRIC GLIOMAS MAY LACK ANGIOCENTRIC GROWTH AND INSTEAD SHOW A VARIETY OF GROWTH PATTERNS
Authors: L Stegat, J L Rohwer, D Stichel, D Schrimpf, R Coras, M Pagès, A Tauziède-Espariat, P Varlet, V H Hans, J Meyer, J Schittenhelm, O Staszewski, E Cheesman, M Glatzel, S Schmid, P Wesseling, A Korshunov, A Sexton-Oates, U Schüller, L Kõrgvee, S Mueller, A Olar, M Snuderl, L Schweizer, E Aronica, F Sahm, A von Deimling, I Blumcke, D T W Jones, D Capper, A K Wefers
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Angiocentric glioma mainly occurs in children and young adults. It is associated with a good prognosis (CNS WHO grade 1). Molecularly, most angiocentric gliomas have a MYB-QKI fusion. Histologically, angiocentric gliomas were initially defined by angiocentric growth of the tumor cells. However, we noticed that epigenetically defined angiocentric gliomas often get different diagnoses based on their histology as they may lack this angiocentric growth pattern. We therefore wanted to further analyze epigenetically defined angiocentric gliomas and evaluate how reliable these gliomas are histologically diagnosed based on the criteria defined by the WHO. MATERIAL AND METHODS We collected 48 epigenetically defined angiocentric gliomas (37 supratentorial, 11 infratentorial) from 46 patients with sufficient tissue for histological and molecular analyses (DNA methylation analyses; RNA sequencing of a subset). The classification was done using unsupervised hierarchical cluster analyses from DNA methylation data and the brain tumor classifiers v11b4 and v12.5 (www.molecularneuropathology.org). RESULTS Angiocentric gliomas were epigenetically distinct from other gliomas including the diffuse astrocytomas, MYB- or MYBL1-altered. A MYB-QKI fusion was detected in 69% (n = 18/26) of angiocentric gliomas, confirming the diagnosis. Other fusions detected were fusions of MYB with intergenic sites, mainly close to QKI (19%; n = 5/26), and MYBL1-QKI (8%; n = 2/26). Histological workup revealed that 75% of the cases included in this study showed the typical angiocentric growth pattern. However, in many of these tumors this was not very pronounced. Many angiocentric gliomas displayed an unspecific growth pattern or resembled pilocytic astrocytoma or ependymoma. Hence, about 59% of angiocentric gliomas were initially misdiagnosed without molecular analyses (supratentorial 50%, infratentorial 100%). We obtained similar results expanding the cohort with further epigenetically defined angiocentric gliomas for which no tissue for a histological re-evaluation was available (total 68 cases; 50 supratentorial, 12 infratentorial; 65 patients). In this expanded cohort, 54% of cases were initially misdiagnosed (45% of supratentorial and 100% of infratentorial cases). CONCLUSION In summary, we show that angiocentric glioma often does not show the typical angiocentric growth pattern, resulting in different diagnoses in more than 50% of the cases without molecular analyses. Thus, DNA methylation analyses are needed for a reliable diagnosis of this tumor type.
P11.33.B A PATIENT WITH GLIOBLASTOMA AND EXTENSIVE EXTRANEURAL METASTASES - DOES MOLECULAR BIOLOGY PLAY A CRUCIAL ROLE?
Authors: E Moen Taule, J Brekke, H Miletic, H Sætran, S Maric, I HogenEsch, R Mahesparan
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Extraneural metastases of glioblastoma (GBM) are rare, reported incidence in literature is 0.4% to 2%. There is a lack in epidemiological data, and what little exists is outdated. The most commonly reported sites of metastases are bone, lymph node and lung. There is an insufficient understanding of the biological mechanism of metastasis, nevertheless, surgical intervention and peritoneal seeding through a ventriculoperitoneal shunt have been postulated as rational routes for the tumor cells. However, reports show metastasizing GBM in patients where neither of these procedures have been performed and therefore biological aspects should be elucidated. Previously, some few genomic studies have shown high mutational burden and that some mutations are only detected in the metastases, indicating clonal evolution. Commonly TP53, TERT, PTEN and CDKN2A/B have been revealed as shared mutations. MATERIAL AND METHODS A 55-year-old man presented with approximately 2 months of progressive headache and behavioral changes. Brain MRI revealed a left temporal lesion suspicious of GBM and no extracranial metastasis was detected. The patient underwent near total surgical resection and completed Stupp protocol. Nine months later, he was admitted to the local hospital with reduced general condition, tachypneic and lower back pain, but subsequent CT of thorax and abdomen revealed multiple pathological lesions in mediastinum, bones, lung, soft tissue, and mesentery. MRI confirmed the findings and a large soft tissue lesion at the level of the 6th thoracic vertebrae, was biopsied and showed metastasis from GBM. There was also local progression of the primary tumor in the brain. Treatment strategy was changed to a combination of lomustine, vincristine and bevacizumab. It was collected blood samples from the patient in respect of circulating tumor cells. A molecular characterization of the tumor samples was performed. RESULTS The primary tumor was MGMT promotor methylated, IDH-1/-2 wildtype, had no TERT promotor mutation, TP53 wildtype and ATRX was intact. The biopsy of the paravertebral lesion showed infiltration of a low differentiated, highly cellular tumor. Immunohistochemically the tumor cells were positive for GFAP, OLIG2 and S100. The molecular features revealed no mutation in BRAF or NTRK. Interestingly, PD-L1 was extremely upregulated, may indicating a potential benefit of immune-checkpoint inhibitors for extraneural metastases. A literature survey is done to find out any risk factors for metastasis. CONCLUSION We report a rare case of GBM with extensive extraneural metastases. This underlines the importance of comparing molecular biology, localization, and other patient and tumoral factors in order to identify any specific risk factor for metastasis. In turn, helping to stratify the follow up of this subgroup in the future.
P12.11.B THE BIOLOGICAL CHARACTERISTICS OF HUMAN GLIOBLASTOMA ASSOCIATED MESENCHYMAL STEM CELLS
Authors: Y Yu, J Wang, Z Chen
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Mesenchymal stem cells (MSCs) have been identified existing in the tumor microenvironment (TME) as one of the important stromal cells and can be isolated from various tissues. Recently, it has been reported that tumor-associated MSCs (TA-MSCs) are involved in tumorigenesis. Experimental studies revealed MSCs in glioblastoma progress with numerous controversies. The aim of this study was to determine the characteristics and clarify functions of MSCs in the glioblastoma microenvironment. MATERIAL AND METHODS Herein, 32 surgical specimens from patients with high-grade glioma were collected for primary culture of glioma mesenchymal stem cells (GMSCs). After being cultured for 3 passages, the surface antigens of GMSCs were identified by flow cytometry and the trilineage differentiation ability was determined in vitro. The related gene expression on RNA and protein levels was detected by PCR and flow cytometry. Proliferation, cell cycle, migration and invasion assays were used to make sure the characteristics of GMSCs. In addition, the effects of GMSCs on glioma cells were detected both in vitro and in vivo. RESULTS We observed that GMSCs showed a typical spindle-like shape and multipotency in vitro, similar to MSCs derived from bone marrow (BMSCs). GMSCs were strongly positive for the mesenchymal markers, especially CD90(Thy-1), while the expression amount for CD44, SOX2 and Nucleostemin were consistent among BMSCs, glioma cell line and primary tumor cells. Additionally, the results of proliferation, migration and invasion assays indicated GMSCs was a group of normal stem cells. We also demonstrated that GMSCs could promote GBM malignant progression by enhancing the migrative ability of tumor cells. CONCLUSION We successfully isolated and identified GMSCs from glioblastoma primary culture. The results verified the characteristics of GMSCs were similar to BMSCs, but different from glioma cells. Taken together, MSCs exist in the glioblastoma tumor microenvironment and they may play a crucial role in tumor initiation and invasive growth, which might serve as a potential target for cancer therapy.
P11.43.B HIGH-RESOLUTION NERVE ULTRASOUND IN NEUROFIBROMATOSIS TYPE 1
Authors: D C Noordhoek, E Mann, T Ennik, S A van Dijk, J Drenthen, W Taal
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Patients with neurofibromatosis type 1 (NF1) can develop plexiform neurofibromas (PN). PN are peripheral nerve sheath tumors that can cause pain, neurological deficit and can transform into malignant peripheral nerve sheath tumors (MPNST). High-resolution ultrasound (HRUS) is suggested as a quick and cost-effective technique, as compared to whole-body MRI, for screening NF1 patients for PN. Our aim is to describe the variety of HRUS nerve abnormalities in NF1 patients and to study the link between nerve morphology and nerve function. MATERIAL AND METHODS We selected patients with a clinical diagnosis of NF1, with or without symptoms related to the peripheral nervous system (PNS) such as pain, sensory disturbances or loss of strength. Patients were invited for a study visit including neurological examination, nerve conduction studies (NCS) and HRUS. One-sided NCS were performed of the median and ulnar nerve (motor and sensory), peroneal and tibial nerve (motor) and sural nerve according to standard protocol. We visualised the brachial plexus, median-, radial-, ulnar-, peroneal-, tibial-, and sural nerves on both sides using HRUS. The cross-sectional area (CSA) of the nerve was measured at predefined anatomical sites, and additional sites in case of focal nerve enlargement. RESULTS We enrolled 60 NF1 patients, of which 57% had PNS-related symptoms. One third of our patients had neurological deficits during physical examination. We found nerve enlargement with HRUS in 48 out of 60 patients (80%), this was not significantly different between patients with PNS symptoms or without PNS symptoms (82% vs 77% respectively, p=0.602). In 82% of the patients with PNS symptoms, their symptoms were likely to be related to one or more nerve enlargements. Nine of these patients had clinical and neurophysiological signs of carpal tunnel syndrome. Different patterns of nerve enlargement were identified. 46% had isolated nerve enlargements, 25% had diffusely enlarged nerves and 29% had a mixture of diffusely enlarged nerves with isolated nerve enlargements. The majority of the patients with nerve enlargement on HRUS had no abnormalities on NCS (65%). CONCLUSION The majority of NF1 patients have nerve enlargements as seen by HRUS, however we have shown that nerve enlargements can often be asymptomatic and do not always lead to impaired nerve function. To determine whether patients have PN cannot be based solely on clinical evaluation of symptoms. HRUS might have an application as a screening tool for NF1 patients in clinical practice. However, further research is needed to describe growth of nerve enlargements, the impact of intra- and interobserver variability on CSA measurements and to improve our knowledge on the link between nerve morphology and nerve function in NF1.
P10.31.A OSIMERTINIB AND OTX008 IMPAIR SURVIVAL OF GLIOBLASTOMA CELLS BY INHIBITING RAS
Authors: M Barthelmay, H Goett, M Kolodziej, M Stein, E Uhl
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Tyrosine kinase receptors play a critical role in the progression of almost all malignancies. In 83% of glioblastoma the endothelial growth factor receptor (EGFR) is affected by genetic alterations leading to cell proliferation and therapy resistance. This leads to a constitutive activation of EGFR, following the activation of the PI3K/AKT and RAS/MAPK signalling pathways. The EGFR-inhibitor Osimertinib showed anti-tumor effect in lung cancer patients with cerebral metastasis. OTX008 is a selective inhibitor of Galectin-1, a small protein, which is involved in stabilising the active form of H-Ras and thereby enables the downstream PI3K/AKT and RAS/MAPK pathways. This study was performed to investigate whether OTX008, Osimertinib and a combination of both have an antiproliferative effect and inhibit the Ras downstream signalling pathways in glioblastoma cells. MATERIAL AND METHODS U87 and A172 glioblastoma cells were grown to 80% confluence and treated with Osimertinib in concentrations ranging from 3 μM to 7 μM. After 72 hours cell viability was quantified via XTT-assay. Dose-response curves were calculated by probit analysis. For investigation of the inhibitory effect of OTX008 and Osimertinib on the constitutive activation of Ras U87 cells were treated with 15 μM OTX008, 3 μM Osimertinib, a combination of 15 μM OTX008 and 3 μM Osimertinib and a combination of DMSO and hydrochloricacid. After 72 hours the cells were collected and lysed using Active Ras Detection Kit from Cell Signaling Technology for western blot analysis. RESULTS Osimertinib reduced cell survival in all tested glioblastoma cell lines with a mean ED50 of 6.81 (95%CI: 6.75-6.86) μM. Using western blot analysis to evaluate the effect on the effector protein Ras at the beginning of the PI3K/AKT and RAS/MAPK pathways the effect of OTX008 and Osimertinib on the proliferation of glioblastoma cell line U87 was shown with the inhibition of Ras. CONCLUSION The constitutive activation of the PI3K/Akt and RAS/MAPK pathways is associated with uncontrolled cell growth and therapeutic resistance. The EGFR-inhibitor Osimertinib and the selective Galectin-1 inhibitor OTX008 showed antiproliferative effect in immortalized glioblastoma cell line U87 and were also able to inhibit activation of Ras. Future experiments should focus on the downstream signalling of the pathways, especially in EGFR mutated glioblastoma stem cells.
P01.01.A THE IMPACT OF BRAIN LESIONS ON HEALTH-RELATED QUALITY OF LIFE IN PATIENTS WITH WHO CNS GRADE 3 OR 4 GLIOMA: A LESION-FUNCTION AND RESTING-STATE FMRI ANALYSIS
Authors: M Kocher, A Heinzel, F M Mottaghy, C Filss, G Stoffels, P Lohmann, M Friedrich, N J Shah, S Caspers, C Weiss Lucas, M I Ruge, N Galldiks, G R Fink, K Langen
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND In glioma patients, tumor development and multimodality therapy are associated with changes in health-related quality of life (HRQoL). It is largely unknown how different types and locations of tumor- and treatment-related brain lesions, as well as their relationship to white matter tracts and functional brain networks, affect HRQoL. MATERIAL AND METHODS In 121 patients with pretreated gliomas of WHO CNS grades 3 or 4, structural MRI, O-(2-[18F]fluoroethyl)-L-tyrosine (FET) PET, resting-state functional MRI (rs-fMRI) and self-reported HRQoL questionnaires (EORTC QLQ-C30/BN20) were obtained. Resection cavities, T1-enhancing lesions, T2/FLAIR hyperintensities, and lesions with pathologically increased FET uptake were delineated. Effects of tumor lateralization, involvement of white matter tracts or resting-state network nodes by different types of lesions and within-network rs-fMRI connectivity were analyzed in terms of their interaction with HRQoL scores. RESULTS Right hemisphere gliomas were associated with significantly less favorable outcomes in physical, role, emotional and social functioning, compared with left-sided tumors. Most functional HRQoL scores correlated significantly with right-sided white-matter tracts involvement by T2/FLAIR hyperintensities and with loss of within-network functional connectivity of right-sided nodes. Tumors of the left hemisphere caused significantly more communication deficits. CONCLUSION In pretreated high-grade gliomas, right hemisphere lesions are associated with reduced HRQoL scores in most functional domains except communication ability, compared to tumors of the left hemisphere. These relationships are mainly observed for T2/FLAIR lesions involving structural and functional networks in the right hemisphere. The data suggest that sparing the right hemisphere from treatment-related tissue damage may improve HRQoL in glioma patients.